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Genetic Pathways of Human Cytomegalovirus Drug Resistance

人类巨细胞病毒耐药性的遗传途径

基本信息

批准号：
10557876
负责人：
Sunwen Chou
金额：
$ 31.2万
依托单位：
PORTLAND VA RESEARCH FOUNDATION, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557876
关键词：
Alternative Therapies Antiviral Agents Antiviral Therapy Area Cells Cidofovir Cytomegalovirus Cytomegalovirus Infections DNA Polymerase Inhibitor DNA-Directed DNA Polymerase Data Development Diagnosis Disease Drug Exposure Drug resistance Evolution Exposure to Foscarnet Future Ganciclovir Genes Genetic Genetic Polymorphism Genotype Human Immunocompromised Host In Vitro Laboratories Malignant Neoplasms Mission Morphologic artifacts Mutation Opportunistic Infections Oral Pathway interactions Pharmaceutical Preparations Phenotype Phosphotransferases Point Mutation Predisposition Prodrugs Prophylactic treatment Recombinants Research Resistance Resistance profile Specimen Testing Therapeutic Toxic effect Transplant Recipients Tropism Valganciclovir Variant Viral active method anti-viral efficacy clinical diagnosis clinical diagnostics clinical practice comparative cost deep sequencing design drug candidate experience fitness improved in vivo inhibitor kinase inhibitor maribavir novel phase III trial receptor resistance gene resistance mechanism resistance mutation stem cells terminase viral DNA viral detection whole genome

项目摘要

Project Summary Toxicity and drug resistance limit the efficacy of antiviral therapy for cytomegalovirus (CMV) disease in immunosuppressed hosts such as cancer and transplant recipients. Current therapy includes DNA polymerase inhibitors ganciclovir, foscarnet and cidofovir. The terminase inhibitor letermovir was recently approved for prophylaxis, and the UL97 kinase inhibitor maribavir has completed Phase 3 trial as alternative therapy. In clinical practice, CMV drug resistance cannot be diagnosed by direct phenotypic testing of viral isolates, and instead is dependent on an accurate correlation of detected viral mutations and associated resistance phenotypes. The objective of this research is to determine the genetic mechanisms of CMV drug resistance in order to improve clinical diagnosis and the development of new antivirals. Many resistance mutations and polymorphisms in the CMV UL97 kinase, UL54 DNA polymerase and UL56/UL89/UL51 terminase genes have been and continue to be phenotyped, with diagnostically important new resistance loci being identified during each project period. Technical advances in recombinant phenotyping and whole genome deep sequencing are facilitating this research. In the upcoming project period, new focus areas include the characterization of mutations selected after drug exposure in genes outside of known antiviral targets, and analysis of the effects of baseline viral strain variation on drug susceptibility. Specific aims are (1) study the evolution and phenotypes of CMV mutations that develop after in vitro or in vivo exposure to antiviral compounds and combinations; (2) evaluate the phenotypic significance of genetic changes identified by viral whole genome deep sequencing that are outside of known antiviral target genes, and (3) determine the impact of baseline viral strain on drug susceptibility phenotypes by characterization of alternative viral clones and host cells.

项目总结